Solid oral pharmaceutical dosage forms, most often in the form of tablets, are a common mode of delivering active agents for the treatment or prevention of diseases and conditions. For a variety of reasons, patients who are prescribed these dosage forms sometimes attempt to split or divide the formulation into multiple units. These reasons include cost containment, as the price of a specified amount of a dosage form in a given strength is often less than double the price (or the same price) as compared to the same amount of dosage forms in half the strength. This provides the incentive for a patient to split their dose under their own initiative, or under the direction of their health care provider. There have also been proposals for mandatory tablet splitting by various state Medicaid programs.
Tablet splitting can be problematic if the patient has cognitive impairment that limits the ability of the patient to understand and remember instructions for tablet splitting; or arthritis or other impairment of manual dexterity; or Parkinson's disease or other tremors; or visual impairment.
Another problem with tablet splitting is overdosing or underdosing as it is often difficult to split tablets with a degree of certainty as to the dose contained in each fragment. This can be a particular issue with respect to active agents with a narrow therapeutic window (e.g., warfarin, levothyroxine and digoxin), where a slight variation in dosing can lead to sub-therapeutic or toxic plasma levels.
Further, the splitting of certain controlled release dosage forms (e.g., opioids, theophylline, calcium channel blockers) compromises the integrity of the dosage form, resulting in the immediate release of an amount of active agent intended for release over an extended period of time. This can also result in toxic plasma levels.
A study of 11 commonly split tablets showed that 8 of the 11 tablets, when split, failed to produce half-tablets that met the content uniformity test for tablets from the United States Pharmacopeia, which requires a discrepancy that falls within 85% and 115% of the intended dosage. Notably, scoring of the tablet did not predict whether the tablet would pass or fail this test. See, Teng et al. Lack of medication dose uniformity in commonly split tablets. J Am Pharm Assoc. 2002; 42:195-9.
Splitting or crushing of dosage forms of drugs susceptible to abuse (e.g., opioid analgesics) is also a common method of abusers to obtain an amount of active agent for illicit use. For example, immediate release opioid formulations can be split or crushed in order to provide the active agent available for parenteral or nasal abuse.
Controlled release opioid formulations can also be split or crushed in order to make the active agent available therein (intended for release over an extended period) available for immediate parenteral, nasal or oral administration.
There is a need in the art for both immediate and controlled release solid oral dosage forms that are resistant to tampering (e.g., splitting or crushing) which minimize the problems associated therewith.
All references disclosed herein are incorporated by reference in their entireties for all purposes.